A Novel Type of PD-L1 Inhibitor rU1 snRNPA From Human-Derived Protein Scaffolds Library
Three marketed anti-PD-L1 antibodies almost have severe immune-mediated side effects. The therapeutic effects of anti-PD-L1 chemical inhibitors are not satisfied in the clinical trials. Here we constructed human-derived protein scaffolds library and screened scaffolds with a shape complementary to t...
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| Auteurs principaux: | , , , , , , |
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| Format: | article |
| Langue: | EN |
| Publié: |
Frontiers Media S.A.
2021
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| Sujets: | |
| Accès en ligne: | https://doaj.org/article/09525b623e454bf2bbae4966a3b7676f |
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| Résumé: | Three marketed anti-PD-L1 antibodies almost have severe immune-mediated side effects. The therapeutic effects of anti-PD-L1 chemical inhibitors are not satisfied in the clinical trials. Here we constructed human-derived protein scaffolds library and screened scaffolds with a shape complementary to the PD-1 binding domain of PD-L1. The RNA binding domain of U1 snRNPA was selected as one of potential binders because it had the most favorable binding energies with PD-L1 and conformed to pre-established biological criteria for the screening of candidates. The recombinant U1 snRNPA (rU1 snRNPA) in Escherichia coli exhibits anti-cancer activity in melanoma and breast cancer by reactivating tumor-suppressed T cells in vitro and anti-melanoma activity in vivo. Considering hydrophobic and electrostatic interactions, three residues were mutated on the interface of U1 snRNPA and PD-L1 complex, and the ranked variants by PatchDock and A32D showed an increased active phenotype. The screening of human-derived protein scaffolds may become the potential development of therapeutic agents. |
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